The NOD receptors are cytoplasmic pattern recognition receptors whose primary function has been thought to be the innate recognition of bacterial cell wall peptidoglycans. As described in last years report and summarized below in Scientific Advances, Chiaki Iwamura asked whether NOD stimulation might play a role in hematopoiesis. In particular he focused on mesenchymal stromal cells that are known to produce a wide variety of different cytokines many of which also have a role in steady-state homeostasis. He demonstrated that NOD1 ligand administration to germ-free mice restored the numbers of hematopoietic stem cells (HSC) and precursors in bone marrow as well as serum concentrations of hematopoietic cytokines to the levels displayed by specific pathogen free control animals thus arguing for a a major role for this pathway in the regulation of hematopoiesis by the microbiota. Interestingly, he showed that the effect of NOD1 stimulation was indirect and targeted bone marrow mesenchymal stromal cells which respond by producing cytokines (IL-7, Flt3L, SCF, ThPO and IL-6) that in turn stimulate hematopoietic expansion. In addition to discovering a role for NOD-1 expressed in MSC in determining the influence of the microbiota on optimal hematopoiesis, Dr. Iwamura has more recently found that this innate receptor plays an equally important microbiota independent function in hematopoetic cells themselves. He observed that the thymus, spleen and lymph nodes of nave NOD1-/-mice display significantly reduced cellularity due to decreased numbers of lymphocytes (T, B and NK cells). Bone marrow (BM) reconstitution experiments demonstrated that this deficiency is due to lack of NOD1 in the hematopoetic compartment, while additional experiments excluded the contribution of the microbiota and the decreased serum levels of hematopoietic cytokines. The defect in hematopoietic cells of NOD1-/-mice was even more accentuated in competitive BM chimera experiments. Interestingly, these defects were amplified in a NOD1-/-mouse strain (delta CARD NOD1) that expresses a truncated form of NOD1 lacking the CARD signaling domain but which we propose functions as a dominant negative variant. In addition to their impaired lymphopoietic potential, CD4+T lymphocytes from NOD1-/-mice were hyporesponsive when TCR stimulated in the presence of IL-2. Taken together, his findings reveal a cell intrinsic role for NOD1 in lymphocyte homeostasis and CD4+T cell function that is likely to involve recognition of an endogenous, as opposed to microbial, ligand. Current experiments suggest that this ligand may be a component of the STAT-5 signaling pathway which is know to play a major role in both steady-state and antigen induced lymphocyte differentiation and expansion. Indeed in parallel experiments, Nod-1 deficient mice were shown to display increased susceptibility to infection with Toxoplasma gondii and this correlated with blunted T cell responses to the parasite. As discussed in last years report, we have been examining the interaction of the host gut and pulmonary microbiota on Mtb infection as well as the effects of Mtb chemotherapy on the microbiota and the possible influence of such changes on immunological responsiveness to infection and the pharmacokinetics of the TB drugs themselves. Our work had indicated that the standard TB drugs (isoniazid, pyrazinamide and rifampicin) given to patients as a cocktail induce major reproducible changes in the distribution of gut bacterial species in mice as determined by 16s RNA sequencing as early as 2 weeks post-treatment and that this dysbiosis persists for at least 3 months after the cessation of antibiotic administration (Namasaviyam et.al., Microbiome, 2017). At the same time clinical collaborators, comparing treated and untreated TB patients in a cross-sectional study in Haiti, observed a similar dysbiosis lasting for at least one year after the completion of chemotherapy and involving many of the same taxa altered in treated mice (Wipperman et al., Sci. Reports, in press).